Important strides have been made recently in uncovering the molecular mechanisms of learning and memory in the brain. However, a number of observations (such as memory in plants and protozoa, and the occasional hydrocephalic patient with <30% of the cortex of a chimpanzee but above-normal intelligence) suggest that we have much to learn about the substratum of memories and the mechanisms by which information is stored and retrieved within biological tissues. The flatworm provides an unprecedented opportunity to make progress in this area because Planaria, our distant ancestors, are a tractable system featuring cephalization, a bilateral body-plan, astounding powers of regeneration, and the ability to learn. Research performed almost 50 years ago revealed that when worms were trained on a simple task, cut in half, and allowed to regenerate complete worms from the tail and head end, worms resulting from the tail fragment exhibited recall of the information learned. This simple observation is truly grand in its implications, because it suggests that a) memories may be stored outside the brain, and b) whatever structure/process retains the information, it is able to impose it on the regenerating brain resulting in appropriate changes in behavior of the organism. The field languished because of a focus on poorly controlled cannibalism studies motivated by models of memory storage in RNA. However, the availability of modern techniques now affords us the opportunity to use this context to uncover novel mechanisms by which cells and tissues can store information and exchange signals during morphogenesis, patterning, and regeneration. We propose two aims to establish a foundation for the study of mechanisms of information storage outside the brain: (1) Build a computer-driven learning device and develop training/recall protocols which avoid all of the major problems of previous studies in this field, and (2) Establish unequivocally whether the tail fragment contains learned information and can impose it on the regenerating brain. The development of an automated learning station and its application to this uniquely appropriate model may allow us to rigorously demonstrate memory storage outside of the brain. This proposal fits well into the "high-risk", "high-reward" designation of the R21 program. It is high-risk because (1) no other lab has published on this topic in decades (it is a radical departure from the current focus on mammalian or Aplysia systems), (2) the outcome is uncertain because virtually nothing is known about how information can be stored outside the brain, and (3) new techniques may need to be developed to pursue the findings to their ultimate conclusion. It is high-reward because the identification and characterization of information storage outside of the brain is a completely novel mechanism which would make fundamental contributions to basic neurobiology, the understanding of memory and learning in mammals (including man), the biomedicine of memory disorders and neurological birth defects, the ethology of invertebrates, and the engineering and computer science of artificial memory systems (including bioengineering of prosthetic memory devices). Most importantly, this work will have significant implications for the understanding of basic cell biology and signaling during regeneration, in revealing how non-neuronal cells retain and pass on information. The device and protocols we propose will ultimately also enable powerful large-scale pharmaceutical screens of drug and proteomic libraries to identify novel psychoactive compounds of high biomedical relevance to human beings. [unreadable] [unreadable]